Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma

ObjectiveThe lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC.DesignA...

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Veröffentlicht in:Gut Jg. 68; H. 12; S. 2195 - 2205
Hauptverfasser: Cai, Jiabin, Chen, Lei, Zhang, Zhou, Zhang, Xinyu, Lu, Xingyu, Liu, Weiwei, Shi, Guoming, Ge, Yang, Gao, Pingting, Yang, Yuan, Ke, Aiwu, Xiao, Linlin, Dong, Ruizhao, Zhu, Yanjing, Yang, Xuan, Wang, Jiefei, Zhu, Tongyu, Yang, Deping, Huang, Xiaowu, Sui, Chengjun, Qiu, Shuangjian, Shen, Feng, Sun, Huichuan, Zhou, Weiping, Zhou, Jian, Nie, Ji, Zeng, Chang, Stroup, Emily Kunce, Zhang, Xu, Chiu, Brian C-H, Lau, Wan Yee, He, Chuan, Wang, Hongyang, Zhang, Wei, Fan, Jia
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.12.2019
BMJ Publishing Group LTD
BMJ Publishing Group
Schriftenreihe:Original article
Schlagworte:
5-Methylcytosine - analogs & derivatives
5-Methylcytosine - blood
Biomarkers
Biomarkers, Tumor - blood
Biopsy
cancer
Carcinoma, Hepatocellular - blood
Carcinoma, Hepatocellular - diagnosis
Carcinoma, Hepatocellular - genetics
Cell-Free Nucleic Acids - blood
Chronic infection
Cirrhosis
Clinical outcomes
Deoxyribonucleic acid
DNA
DNA, Neoplasm - analysis
Early Detection of Cancer - methods
Epigenetics
Female
Gastroenterology
Gene expression
Gene mapping
Generalized linear models
Genome-Wide Association Study - methods
Genomes
Health care
Hepatitis
Hepatitis B
hepatobiliary cancer
Hepatocellular carcinoma
Hepatology
Hospitals
Humans
Liver cancer
Liver cirrhosis
Liver Neoplasms - blood
Liver Neoplasms - diagnosis
Liver Neoplasms - genetics
Male
Medical prognosis
Middle Aged
Patients
Prospective Studies
ROC Curve
Signal transduction
Surveillance
Tumors
α-Fetoprotein
Chicago Illinois
United States > US
Illinois
China
hepatobiliary cancer
cancer
hepatocellular carcinoma
ISSN:0017-5749, 1468-3288, 1468-3288
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Zusammenfassung:ObjectiveThe lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC.DesignApplying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection.ResultsThe 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history).ConclusionWe have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.
Bibliographie:Original article
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0017-5749
1468-3288
1468-3288
DOI:10.1136/gutjnl-2019-318882